17β-Estradiol inhibition of PPARγ-induced adipogenesis and adipocyte-specific gene expression

Aim: To investigate the molecular interaction of peroxisome proliferator-activated receptor gamma (PPAR gamma) with 17 beta-estradiol (E) in the regulation of adipogenesis. Methods: Female ovariectomized (OVX) mice and differentiated 3T3-L1 adipocytes were treated with combinations of the PPAR gamma agonist troglitazone or E, and the variables and determinants of adipogenesis were measured using in vivo and in vitro approaches. Results: Troglitazone (250 mg.kg(-1).d(-1) for 13 weeks) decreased the size of adipocytes without the change in white adipose tissue (WAT) mass and increased the expression of adipocyte-specific genes, such as PPAR gamma, adipocyte fatty acid binding protein, and lipoprotein lipase, compared with OVX control mice. E (0.05 mg/pellet, sc implanted) significantly reduced WAT mass, adipocyte size, and adipose marker gene expression. When mice were concomitantly treated with troglitazone and E, E blunted the effects of troglitazone on WAT mass, adipocyte size, and adipose PPAR gamma target gene expression. Consistent with the in vivo data, E (10 mu mol/L) treatment inhibited lipid accumulation and the expression of adipocyte-specific genes caused by troglitazone (10 mu mol/L) in 3T3-L1 cells. E (10 mu mol/L) also decreased troglitazone-induced PPAR gamma reporter activity through both estrogen receptor (ER) alpha and ER beta. Mechanistic studies indicated that E (0.1 mu mol/L) decreased the DNA binding of PPAR gamma induced by troglitazone (1 mu mol/L) and inhibited the recruitment of the PPAR gamma coactivator CREB-binding protein. Conclusion: These results suggest that in vivo and in vitro treatment of E interferes with the actions of PPAR gamma on adipogenesis by down-regulating adipogenesis-related genes, which are mediated through the inhibition of PPAR gamma coactivator recruitment. In addition, it is likely that the activities of PPAR gamma activators may be enhanced in estrogen-deficient states.